The present invention relates to new uses of certain bile acid or bile salt fatty acid conjugates.
From Israeli Patent Application No. 123.998 there are known bile acid or bile salt fatty acid conjugates [BAFAC I] of general formula IW-X-Gin which G is a bile acid or bile salt radical, which if desired, is conjugated in position 24 with a suitable amino acid, W stands for one or two fatty acid radicals having 18-22 carbon atoms and X stands for a NH bond between said bile acid or bile salt radical and the fatty acid(s).
From said specification there is known the use of the compounds of general formula I and of pharmaceutical compositions comprising same for dissolving cholesterol gallstones in bile, preventing the occurrence or recurrence of said gallstones, and in reducing or preventing arteriosclerosis. There are also known methods for the treatment of said diseases.
It has now surprisingly been found that BAFACS and pharmaceutical compositions comprising same in which W stands for one or two fatty acid radicals having 14-22 carbon atoms and X stands for a suitable bonding member or for a direct C═C bond between said bile acid or bile salt radical and the fatty acid[s] (being compounds of general formula II; hereinafter called BAFACS II) and pharmaceutical compositions comprising same, have additional uses, namely they can be used:
a. for the reduction of cholesterol concentration in blood;
b. for the treatment of fatty liver; and
c. for the treatment of hyperglycemia, insulin resistance and diabetes.
Said BAFACS and pharmaceutical compositions comprising same can also be used. in the treatment of said diseases.
The bond has to be a solid bond that is not substantially deconjugated by intestinal and/or bacterial enzymes during the process of absorption. An ester bond is thus not suitable since it is easily deconjugated. The bond stands in particular for NH but may also stand for other suitable bonding members, e.g. S, P, O-ether, etc.
The bond can be in the alpha or beta configuration and can be attached in various positions of the bile acid molecule, positions 3, 6, 7, 12 and 24 being preferred.
The diseases concerned, the history of the treatment thereof and the new use for the treatment thereof are explained hereinafter:
A. Reduction of Cholesterol Concentration in Blood
Hypercholesterolemia is deleterious to health. It is a causative factor in several major disease processes such as ischemic heart disease, myocardial infarction, peripheral vascular disease, possibly stroke, etc. Reduction of cholesterol concentration in blood is beneficial or preventive in some of said diseases. Current medical treatment of hypercholesterolemia is aimed at reducing endogenous cholesterol synthesis in the liver. The statins used for this purpose inhibit the enzyme HMG CoA Reductase. However, a major portion of body cholesterol originates from dietary cholesterol. Diet restrictions are notoriously ineffective. Ion exchange resins have also been used to bind bile acids (products of cholesterol catabolism) and sequester them in the intestinal lumen leading to their fecal excretion. They have some effect on blood cholesterol but also important side effects which limit their use.
It has now been shown that BAFACs II reduce diet induced hypercholesterolemia in several animal species even as the animals continue to consume the high cholesterol, high fat diet.
B. Treatment of Fatty Liver
Fatty liver is one of the most common liver diseases today. It is due to excessive accumulation of fat in the liver. It is demonstrated histologically by the presence of variable amounts of micro and/or macro vesicular fat droplets in the liver tissue. Fatty liver can be caused by drugs, chemicals, diseases, bacteria, etc. but the main cause is excessive dietary intake leading to (mainly truncal) obesity and insulin resistance.
Due to the increasing prevalence of overweight in affluent societies the prevalence of fatty liver is rising. Fatty liver may progress to steatohepatitis and cirrhosis with the attendant morbidity and mortality.
The best treatment for diet induced fatty liver is sustained weight loss. As is, however, well known this is rarely achieved.
It has now been discovered that BAFACs II can reduce and prevent fatty liver. This has also been demonstrated during continuation of the excessive dietary intake in several animal species.
C. Treatment of Hyperglycemia, Insulin Resistance and Diabetes
Diabetes mellitus is a disorder of carbohydrate (glucose) metabolism. It is schematically divided into type 1, insulin dependent diabetes mellitus (IDDM) characterized by insulin deficiency and type 2, not insulin dependent diabetes mellitus (NIDDM) in which there is mainly insulin resistance. NIDDM is often associated with obesity, insulin resistance and/or fatty liver. There are also other causes of hyperglycemia. Treatment of diabetes mellitus involves diet, insulin injections and/or oral hypoglycemic drugs. The aim of therapy is to normalize blood glucose levels and reduce insulin resistance. Diabetes, particularly poorly controlled diabetes leads to severe complications.
It has now been discovered that BAFACs reduce and normalize blood glucose levels in animal models of IDDM and NIDDM.
In another embodiment, the present invention provides a method for treating a disease or disorder associated with altered glucose metabolism and insulin resistance selected from the group consisting of hyperglycemia, diabetes, insulin resistance and obesity. In another embodiment, the disease or disorder associated with altered glucose metabolism is selected from hyperglycemia, insulin resistance and diabetes. In another embodiment, said diabetes is selected from IDDM and NIDDM.
In another embodiment, the method of the present invention is for lowering said subject body weight. In another embodiment, said subject is a human.